Abstract Epigenetic remodeling of gene expression is a powerful therapeutic approach whose potential has yet to be fully exploited. A number of degenerative diseases of the retina are good candidates for this approach and this proposal focuses Retinitis Pigmentosa (RP), for which there are both excellent animal models and an available patient population, but no treatments. In RP, mutant genes lead to the death of rod photoreceptors and a secondary death of nearby cone photoreceptors that leads to blindness. Based on preliminary data we have proposed the hypothesis that selective pharmacological manipulation of histone modifying enzymes will alter the epigenetic landscape and lessen the impact of deleterious mutations, allowing extended survival of rod photoreceptors in RP. To test this hypothesis we propose three specific aims. First, we will extend our preliminary findings to more fully define the optimum time course and dose of LDS1 inhibitors (TCP and GSK2879552) that can block rod degeneration in the rd10 model of RP. We will quantitate photoreceptor survival by immunocytochemistry, quantitative PCR, and OCT. We will also measure visual function using ERG. We will use a second model of RP, the rd3 mouse, to test whether the effects can be generalized to multiple forms of RP. Second, we will examine whether HDAC1 specific inhibitors can provide protection to rods in the same models of RP. In a second series of experiments we will test whether use of LSD1 and HDAC1 inhibitors together act synergistically to provide greater protection than either drug alone. Photoreceptor survival and function will be monitored in the same way as in Aim 1. Third, we will analyze whether the epigenetic modifiers act to alter expression of the mutant genes and gene in the same network, or have broader effects on processes such as apoptosis and inflammation. We will use RNA-seq methods to give an unbiased measure of changes in gene expression induced by the LSD1 and HDAC1 inhibitors. Key changes will be verified by qPCR. We will also measure changes in cytokines in the retina and the vitreous to provide a quantitative estimate of levels of pro- and anti-inflammatory cytokines, and changes in the activity of key signal pathways. Additionally, we will test whether changes in transcript or protein levels are due to direct changes on the gene epigenetic status, by carrying out ChIP-seq for H3K4me2 (LSD1 substrate) and H3K9ac/12ac (HDAC1 substrate) as measures of promoter accessibility. These experiments will provide insights into the mechanisms of protection and by analyzing the cellular networks most altered will provide new targets for even more specific therapy. Overall, these experiments will provide important information about pathways that can prevent damage in the retina and also offer a novel therapeutic approach that can combat RP and other retinal degenerations.